System for infusing insulin to a subject to imporve impaired total body tissue glucose processing

ABSTRACT

The present invention is a system for delivering insulin to a subject to improve impaired total body tissue glucose processing. The system delivers one or more pulses of insulin to the subject over a period of time accompanied by ingestion of glucose in the form of a carbohydrate containing meal. The number of pulses, the amount of insulin in each pulse, the interval between pulses and the amount of time to deliver each pulse to the subject are selected so that total body tissue processing of glucose is restored in the subject. In subjects whose total body tissue glucose processing has been restored, there is a subsequent fall in circulating blood glucose levels of 50 mg/dl or more primarily and directly as a result of improved total body tissue glucose processing.

FIELD OF INVENTION

The present invention is a system for delivering a series of pulses ofinsulin over a period of time to a subject to improve impaired totalbody tissue glucose processing. More specifically, the number of pulses,the amount of insulin in each pulse, the interval between pulses and theamount of time to deliver each pulse to the subject are selected suchthat the subject's total body tissue processing of glucose is restored.In subjects whose total body tissue glucose processing has been restoredthere is a subsequent fall in circulating blood glucose levels of 50mg/dl or more primarily and directly as a result of improved total bodytissue glucose processing being restored to a number of tissue includingbut not limited to the liver, muscle, heart, kidney, eye, brain, skin,gastrointestinal tract and nerves.

BACKGROUND OF THE INVENTION

Diabetic retinopathy is a major cause of blindness. While earlierdetection and major advances in laser therapies have made significantimpact on this chronic complication of diabetes, the number of diabeticpatients suffering from diabetic retinopathy continues to increase.

Glucose control is typically measured by a blood test, which determinesthe level of hemoglobin A1c, which has been the desired result oftherapy in diabetic patients for many years. However, it is clear thattight circulating glucose control was insufficient in 25% or more of thestudy participants to protect them from the onset or progression ofdiabetic retinopathy, nephropathy or neuropathy.

A major cause of death for patients with diabetes mellitus iscardiovascular disease in its various forms. Existing evidence indicatesthat diabetic patients are particularly susceptible to heart failure,primarily in association with atherosclerosis of the coronary arteriesand autonomic neuropathy. There is little doubt that a metaboliccomponent is present in various forms of cardiovascular disease indiabetic patients. Cardiac dysfunction (lower stroke volume, cardiacindex and ejection fraction and a higher left ventricular end diastolicpressure) frequently manifested by patients with diabetes, can beexplained at least partially by metabolic abnormalities, and is likelysecondary to insulin deficiency since appropriate insulin administrationcan restore normal patterns of cardiac metabolism (Avogaro et al, Am JPhysiol 1990, 258:E606-18).

The pathophysiology of diabetic nephropathy is only partiallyunderstood. The most consistent morphologic finding in diabeticnephropathy is the enlargement of the mesangium, which can compress theglomerular capillaries and thus alter intraglomerular hemodynamics.

Diabetes is the number one cause of non-traumatic amputations. Thecommon sources of amputations are wounds that will not heal and progressto necrosis and gangrene. It is generally observed that diabeticpatients have greater difficulty in healing and in overcominginfections. Diabetes in general and poor circulating glucose control inparticular are thought to be causally related to poor wound repair indiabetic patients. Poor circulating glucose control is also a source ofa lack of energy and a general feeling of malaise.

As reported in Diabetes mellitus and the risk of dementia A. Ott, R P.Stolk, F. Van Harskamp, The Rotterdam Study, Neurology, 1999, vol. 53,pp. 1937-1942, patients with diabetes have an increased risk ofdementia. Having diabetes almost doubled the risk of having dementia(the risk was 1.9 times greater). The risk of diabetics gettingAlzheimer's disease was also nearly double. And in diabetics takinginsulin, the risk was over 4 times that in non-diabetics. Even afteradjusting for possible effects of sex, age, educational level and theother factors measured, the findings were the same. Therefore, it can beconcluded that diabetes is a risk factor for the development ofdementias, including Alzheimer's disease.

What is needed is a system which can restore metabolism; increasesretinal and neural glucose oxidation by enhancing pyruvate dehydrogenaseactivity; treats retinopathy and central nervous system disorders;increase stroke volume, improves cardiac index; increases ejectionfraction, and lowers ventricular end diastolic pressure, thus improvingcardiac function, as well as improving the quality of life in diabeticpatients. A similar system is also needed to significantly reverse thecardiac dysfunction common to diabetic patients with heart disease. Thesame system should be capable of providing improved blood glucosecontrol as measured by hemoglobin A1c. Additionally a similar system isneeded to improve the entire metabolic process and through itsmultiplicity of effects on neurovascular reactivity, intraglomerularpressure and hemodynamics, improve intraglomerular hemodynamics, andthus arrest the progression of diabetic nephropathy and reduce the riskof development of End-Stage Renal Disease (ESRD). Further a similarsystem is also needed to increase glucose oxidation in the affectedareas and therefore provide more energy for the same amount of oxygendelivered for treating wounds, promote healing and avoid lower extremityamputations in both diabetic and non-diabetic patients. A system isrequired to improve the metabolism in the brain of individuals sufferingwith any of 1.) a number of diseases causing senile dementia; 2.)injuries or trauma to the brain and 3.) a number of non-diseases, suchas ageing, jet lag and hence improve mental function of individuals inall three categories.

In a previous patent, U.S. Pat. No. 4,826,810, which is herebyincorporated in the description of this invention, the inventordescribes a method of delivering pulses of insulin to a patient afteringestion of a glucose containing meal. The pulses of insulin areadjusted to produce a series of peaks in the free insulin concentrationso that successively there are increasing free insulin concentrationminima between the said peaks. In order to make this a viable treatmentfor clinical purposes there needs to be a simple, low-cost way ofmeasuring free insulin or the biochemical impact of free insulin todetermine said peaks to insure that the correct levels are present toinsure that the dietary carbohydrate processing capabilities of thesubject's total body tissues are activated. The only viable method formeasuring “free” insulin is costly and time consuming, often taking daysto obtain results. In the mean time it is not known whether or not totalbody tissues have been activated. What is needed is a way to determine,in real time while pulses are being administered and the base line offree insulin is rising, that in fact the patient's total body tissueshave been activated.

SUMMARY OF THE INVENTION

Accordingly, the present invention is a system for delivering insulin toa subject to improve impaired total body tissue glucose processing. Thesystem delivers one or more pulses of insulin to the subject over aperiod of time accompanied by ingestion of glucose or a carbohydratecontaining meal. The amount of insulin in each pulse, the intervalbetween pulses and the amount of time to deliver each pulse to thesubject such as a patient are selected so that the total body tissueprocessing of glucose is restored in the subject.

Coincident with or shortly following the establishment of elevatedcirculating glucose levels in the patient, the first pulse of insulindelivery is administered. This pulse of insulin results in a peak “free”insulin concentration in the blood. In the preferred embodiment, whenthe “free” insulin concentration decreases by about 50%, a second pulseof insulin is administered. When the “free” insulin concentration againdecreases by about 50% the next pulse of insulin is administered.Repetition of this process will result in increasing interpeak “free”insulin concentration. The pulses of insulin are regulated so that theinterpeak “free” insulin concentration increases by 1 to 500 μU/ml fromone pulse to the next. In order to activate the total body tissues inthe preferred embodiment, an increasing interpeak “free” insulinconcentration after ingestion of glucose or a carbohydrate containingmeal is required to activate the total body tissues and for thecirculating blood glucose level to drop 50 mg/dl in subjects withimpaired total body tissue glucose processing. However, there are timesthat even though the interpeak “free” insulin levels are rising, they donot rise sufficiently fast to activate the total body tissues. In thosecircumstances the drop in circulating glucose will not fall by 50 mg/dlor more. However, individuals who are very sensitive to insulin, such astype 1 diabetics and normal non-diabetic individuals, may still respondeven though the interpeak “free” insulin levels are not rising very fastand even though the drop in circulating glucose level is less than 50mg/dl.

In an alternate embodiment, the “free” insulin concentration is allowedto decline to baseline levels before the next pulse of insulin isadministered. In another alternative embodiment, the pulse of insulin isadministered over a sufficiently long duration and magnitude or as asingle square wave given over the course of a day. In these alternativeembodiments, total body tissues are activated due to the rate of changeof insulin levels. In these embodiments, the “free” insulin levelconcentration is allowed to return to baseline before the next pulse ofinsulin is administered in order to prevent tachyphyllaxis fromoccurring.

It is desirable to administer the least amount of insulin consistentwith activation of total body tissue glucose processing. However, theamount of insulin required to activate a patient will vary from patientto patient or even from day to day in the same patient. For the samepatient on one day a pulse regimen will be successful in activation oftotal body tissue glucose processing while the same patient on thefollowing day may require significantly more insulin per pulse or morefrequent pulses to attain activation. Measuring “free” insulin levels inthe blood is an expensive and time-consuming procedure, which cannotprovide the necessary information in real time. The current invention isa system to measure in real time when the patient has actually activatedtotal body tissue glucose processing allowing positive confirmation ofsuccessful patient response and signaling when the pulses no longer needto be administered.

In subjects whose total body tissue glucose processing has been restoredthere is a subsequent fall in circulating blood glucose levels of 50mg/dl or more primarily and directly as a result of total body tissueglucose processing being restored. This circulating glucose level iseasy and low cost to obtain, can be done by the carefully trainedpatient easily in a home health care environment under the supervisionof a doctor, and provides information in real time that the total bodytissue glucose processing function is restored. Patients can, withproper education become well trained and fully capable of obtainingtheir own circulating glucose levels without the need of a doctor toassist with the procedure and evaluate the results. Other means todetermine whether the total body tissues have been activated are costly,do not provide information in real time, require a doctor's evaluationor cannot be used in a home health care environment. There must usuallybe more than a minimum of one pulse in the series of insulin pulses; forexample, two, three, four, five or six. In the preferred embodiment ofthe system an infusion device delivers a series of ten pulses over aperiod of one hour. The infusion device is preferably controlled by aprogrammable processor unit, which controls the amount of insulin ineach pulse, the time to deliver each pulse, and the time between pulses.Circulating blood glucose levels can be measured by any appropriatecirculating glucose measuring method including finger stick methods.

DESCRIPTION OF PREFERRED EMBODIMENTS

Accordingly, the present invention is a system for delivering a seriesof pulses of insulin over a period of time to a subject to improveimpaired total body tissue glucose processing. The number of pulses, theamount of insulin in each pulse, the interval between pulses and theamount of time to deliver each pulse to the subject are selected suchthat total body tissue processing of glucose is restored in the subject.The pulses of insulin are accompanied by the ingestion of glucose or acarbohydrate containing meal. Circulating glucose measurements are madeperiodically to insure proper total body tissue processing of glucosehas been restored. In subjects whose total body tissue glucoseprocessing has been restored there is a subsequent fall in circulatingblood glucose levels of 50 mg/dl or more primarily and directly as aresult of improved total body tissue glucose processing. Thisimprovement in the total body glucose processing rate is called“activation”. The invention is referred to as Chronic IntermittentIntravenous Insulin Therapy (CIIIT) also known as Metabolic ActivationTherapy (MAT), Hepatic Activation, Pulsatile Intravenous Insulin Therapy(PIVIT), Pulsatile or Pulse Insulin Therapy (PIT).

The preferred embodiment of the system for delivering insulin pulses toa patient to improve impaired total body tissue glucose processing is asfollows. On the morning of the procedure, the patient is preferablyseated in a blood drawing chair and a 23 gauge needle or catheter ispreferably inserted into a hand or forearm vein to obtain vascularaccess. However, any system of such access may accomplish the neededresult, including indwelling catheters, PICC lines and PORTACATHS. Aftera short equilibration period, the patient is asked to make a circulatingglucose measurement prior to starting the actual infusion of insulin. Asteady baseline circulating glucose level is achieved when two identicalconsecutive measurements taken 5 minutes apart is obtained. It ispreferable that patients have circulating glucose levels close to 200mg/dl prior to using the infusion system. In the case of pregnantdiabetic women, however, every attempt is made to keep the maximumcirculating glucose level to 150 mg/dl or less.

After the circulating glucose measurement has been taken and the patienthas the proper circulating glucose starting level, the patient is askedto consume a liquid or food containing glucose. The amount of glucosegiven to a diabetic patient ranges from 60 to 100 grams, but for smallframed people the amount could be as low as 40 grams of glucose.However, the amount of initial glucose given to the patient may vary.Liquid or food containing glucose is consumed by the patient to preventthe patient from becoming hypoglycemic and also present the body tissueswith a metabolic signal. The preferred liquid or food is GLUCOLA, butany similar type of liquid or high glycemic food, including but notlimited to cake and bread, containing glucose may be given to thepatient. In a non-diabetic patient more glucose may be required than inthe diabetic patient, but the other parameters would remain the same,including the need for a pulsed delivery of insulin.

In the preferred embodiment, pulses of insulin are then administeredintravenously at planned intervals of time, usually every six minutes;however, other intervals may be used from as low as every three minutesup to every 30 minutes or longer. For diabetic patients the amount ofinsulin in each pulse is 10-200 milliunits of insulin per kilogram ofbody weight; for non-diabetic patients lower.

In alternate embodiments, the pulses of insulin may be administered overa substantially long duration and magnitude or as a single square wavegiven over the course of a day.

In the preferred embodiment of the invention, a programmable insulininfusion device is used to deliver intravenous insulin in preciselymeasured pulses. However, any means of infusing measured amounts ofinsulin may be used, including simple injection with a syringe. It ispreferable that the infusion device be capable of providing measuredpulses of insulin on a prearranged interval, so long as there issufficient glucose in the blood to keep the patient from becominghypoglycemic. It is also preferable that the infusion device is capableof delivering the pulses of insulin in as short duration of time aspossible, without adversely affecting the vein at the site of infusionis used. One preferred infusion device is the BIONICA MD-110. However,less accurate devices and slower devices, including a simple syringe,may deliver the pulses of insulin to achieve the needed infusionprofile. In the preferred embodiment, there must usually be more than aminimum of one pulse in the series of insulin pulses; for example, two,three, four, five or six. In the preferred embodiment of the system, theinfusion device delivers a series of ten pulses over a period of onehour.

In the preferred insulin infusion device, programmed values can be inputto a control processor via a keyboard, through firmware in the infusiondevice or by software via a communications link from a higher levelcomputer or any other appropriate input method. Automated entry of bloodglucose levels is also desired. The communications link may also be usedto send alarm and status messages to a higher level computer via anyacceptable communications protocol and medium. Infusion device status,alarm status and circulating-glucose levels, among other parameters ofthe system may be displayed on a display panel of the infusion device.

A circulating glucose measuring instrument, configured to communicatedirectly with the infusion device through the communications link canprovide timely values of circulating glucose. Alternatively, wirelesscommunications systems can send information from a circulating glucosesensor automatically to the infusion device without operatorintervention. Typical circulating glucose sensors include but are notlimited to finger stick devices, non-invasive instruments using nearinfrared spectroscopy or radio frequency, and implanted sensors.Alternatively the circulating glucose signal can come from animplantable system for monitoring pancreatic beta cell electricalactivity in a patient in order to obtain a measure of a patient'sinsulin demand and circulating glucose level. Any other means for eitherdirectly or indirectly obtaining an accurate measure of the change incirculating glucose levels is also acceptable. The communications linkmay also be used to send alarm and status messages to a higher levelcomputer via any acceptable communications protocol and medium.

When the infusion device is initiated, it dispenses the programmed pulseof insulin in the programmed amount of time to the subject. The insulintravels through an infusion tube into a needle that is insertedintravenously into the subject's forearm. The intravenous site can alsobe any convenient location such as the body or hand. The time to delivereach pulse should be as short as possible and at least less than oneminute and preferably on the order of seconds. The infusion devicestatus, alarm status and circulating-glucose levels, among otherparameters of the system may be displayed on a display panel.

In the preferred embodiment the subject's circulating glucose levels aremeasured as frequently as possible. The measurements are eitherautomatically or manually input into the preferred infusion device.Adjustments to ingested glucose and infused insulin are made to producethe desired results of activating the total body tissues without theunwanted side effects of either hypoglycemia or hyperglycemia.

When finger pricks are used to determine the circulating glucose level,it is recommended that readings be taken every 30 minutes. When lessinvasive means of measuring circulating glucose are used, readings canbe taken more frequently, preferably after the infusion of each pulse ofinsulin. In the preferred embodiment, it is recommended that a period ofone to two minutes is allowed after the infusion of each pulse ofinsulin before circulating glucose levels are measured. In patientswhose total body tissue glucose processing has been restored, i.e. bythe 3^(rd) treatment, there may be a fall in circulating glucose levelsby as much as 50-100 mg/dl. In patients who have yet to obtain propertotal body tissue glucose processing by the 3^(rd) treatment, there willbe no fall or a fall considerably less than 50 mg/dl by the 3^(rd)treatment. In the preferred embodiment, the fall in circulating glucoselevels, indicating restoration of total body tissue processing ofglucose, is generally achieved within one to two hours of initiation ofthe first pulse of insulin using the preferred embodiment of thisinvention; however, the time required may be shorter or longer than oneto two hours. It is possible to decrease the amount of insulin in eachpulse and to lengthen the time between pulses so that it takes in excessof two or even three hours or more for a fall of 50 mg/dl to occur. Thelonger the time it takes to activate the patient, however, the longerthe patient must be under treatment and the less desirable the treatmentmay be for some patients. This decrease in circulating glucose level iscaused by the combination of increased glucose utilization by the heart,kidneys, eyes, liver, brain, skin, gastrointestinal tract, nerves andmuscle.

In prototype testing, a commercially available LIFESCAN ONETOUCH ULTRAglucose meter was used to measure the subject's baseline and subsequentcirculating blood glucose level. The glucose meter was calibratedaccording to the manufacturer's recommendations. A blood sampler teststrip was then inserted into the blood glucose meter as directed by themanufacturer. The glucose meter automatically turned on upon properinsertion of the test strip into the meter. This commercially availableglucose meter utilized a lancet to prick the subject's fingertip or arm.After pricking the skin, the user gently massages the area to help forma round drop of blood (about one micro-liter in volume) on the skinsurface. The subject then caused the blood sample to be absorbed ontothe blood sampler test strip per the manufacturer's recommendedprocedure. If adequate blood was absorbed by the blood sampler teststrip, the blood glucose level was automatically calculated and shown onthe instrument's display panel in approximately 5 seconds. If inadequateblood was absorbed by the blood sampler test strip, as indicated by anerror message or an inaccurate test result, the test strip was discardedand entire testing procedure was repeated. Upon removal of the used teststrip, the glucose meter automatically turned off. Although a LIFESCANONETOUCH ULTRA glucose meter was used in prototype testing, anycommercially available blood glucose meter could be used.

Another indication that total body tissue activation has beenreestablished in the preferred embodiment is that gradually the amountof insulin required to reduce the circulating glucose levels by 50 mg/dlor more will decrease with time. Lowering hemoglobin A1c levels are amore mid-term manifestation that total body tissue glucose processinghas been restored. Longer-term manifestations are seen in the decreaseof a number of complications related to diabetes, including but notlimited to retinopathy, nephropathy, neuropathy, hypoglycemia,cardiovascular disease, and hypertension.

In the preferred embodiment, the phase during which a series of pulsesof insulin is administered and glucose ingested lasts typically for 56minutes (ten pulses with a six minute interval between pulses) and isfollowed by a rest period of usually one or two hours. The rest periodallows the elevated insulin levels to return towards baseline. Duringperiods when insulin is not being infused, the intravenous site ispreferably converted to a heparin or saline lock. The entire procedureis repeated until the desired effect is obtained. Typically theprocedure is repeated three times for each treatment day, but can berepeated as few as two times and up to 8 times in one day. Prior to thepatient being discharged from the procedure, whether in the clinic orhome environment, in the preferred embodiment circulating glucose levelsstabilize at 100-200 mg/dl for approximately 30-45 minutes.

Coincident with or shortly following the establishment of elevatedcirculating glucose levels in the patient, the first pulse of insulindelivery is administered. This pulse results in a peak “free” insulinconcentration in the blood. In the preferred embodiment, when the “free”insulin concentration decreases by about 50%, a second pulse of insulinis administered. The concentration of “free” insulin will rise as aresult of the second pulse of insulin. When the “free” insulinconcentration again decreases by about 50%, the next pulse of insulin isadministered. Repetition of this process will result in increasinginterpeak “free” insulin concentration. The pulses of insulin areregulated so that the interpeak “free” insulin concentration increasesby I to 500 μU/ml from one pulse to the next. In order to activate thevarious tissues of the body in the preferred embodiment, an increasinginterpeak “free” insulin concentration after ingestion of a carbohydratecontaining meal is usually required and for the circulating bloodglucose level to drop 50 mg/dl in subjects with impaired total bodytissue glucose processing. However, there are times that even though theinterpeak “free” insulin levels are rising, they may not risesufficiently fast to activate the various tissues of the body. In thosecircumstances the drop in circulating glucose will not reach 50 mg/dl.However, individuals who are very sensitive to insulin, such as type 1diabetics and normal non-diabetic individuals, may still respond eventhough the interpeak “free” insulin levels are not rising very fast andeven though the drop in circulating glucose level is less than 50 mg/dl.

In an alternate embodiment, the “free” insulin concentration is allowedto decline to baseline levels before the next pulse of insulin isadministered. In another alternate embodiment, the pulse of insulin isadministered over a sufficiently long duration and magnitude or as asingle square wave given over the course of a day. In these alternateembodiments, total body tissues are activated due to the rate of changeof insulin levels. In these alternate embodiments, the “free” insulinlevel concentration is allowed to return to baseline before the nextpulse of insulin is administered in order to prevent tachyphyllaxis fromoccurring. In these alternate embodiments, activation may occur at aslower rate. Therefore it may take additional treatments and the timeperiod for administering the treatments may be longer.

Activation of total body tissue occurs for at least the followingreasons. First, biological tissues respond to the rate of change of theinsulin level. Second, the same tissues respond to the absolute increasein peak and interpeak “free” insulin levels. Third, in order to preventtachyphyllaxis there should be a return to baseline “free” insulinconcentrations at some point during the treatment. In the preferredembodiment, “free” insulin concentrations return to baseline at the endof each hour of insulin pulses and approximately 30 to 60 minutes ofrest, depending on the peak free insulin level achieved during thetreatment. The half-life of insulin is 5 minutes.

Activation of total body tissue glucose processing restores metabolism;increases retinal and neural glucose oxidation by enhancing pyruvatedehydrogenase activity; treats retinopathy and central nervous systemdisorders; increases stroke volume, improves cardiac index; increasesejection fraction, and lowers ventricular end diastolic pressure, thusimproving cardiac function. Activation of total body glucose processingsignificantly reverses the cardiac dysfunction common to diabeticpatients with heart disease and also provides improved blood glucosecontrol as measured by hemoglobin A1c. Activation improves the entiremetabolic process and through its multiplicity of effects onneurovascular reactivity, intraglomerular pressure and hemodynamics,improves intraglomerular hemodynamics, and thus arrests the progressionof diabetic nephropathy and reduces the risk of development of End-StageRenal Disease (ESRD). Restoration of impaired total body glucoseprocessing also increases glucose oxidation in the affected areas andtherefore provides more energy for the same amount of oxygen deliveredfor treating wounds, promote healing and avoid lower extremityamputations in both diabetic and non-diabetic patients. Activation alsoimproves the metabolism in the brain of individuals suffering with anyof 1.) a number of diseases causing senile dementia; 2.) injury ortrauma to the brain and 3.) a number of non-diseases, such as aging, jetlag and hence improve mental function of individuals in all categories.

It is desirable to administer the least amount of insulin consistentwith activation of the glucose processing capacity of various bodytissues including but not limited to the liver, muscle, heart, kidney,brain, gastrointestinal tract, skin, and nerves. However, the amount ofinsulin required to activate a patient will vary from patient to patientor even from day to day in the same patient. For the same patient on oneday, a pulse regimen will be successful in activation of total bodytissue glucose processing while the same patient on the following daymay require significantly more insulin per pulse or more frequent pulsesto attain activation. Measuring “free” insulin levels in the blood is anexpensive and time-consuming procedure, which cannot provide thenecessary information in real time. The current invention is a system tomeasure in real time when the patient has actually activated total bodytissue glucose processing, to allow positive confirmation of successfulpatient response and signal when the pulses no longer need to beadministered.

Accordingly, the present invention is used to increase retinal andneural glucose oxidation by enhancing pyruvate dehydrogenase activityand therefore treats retinopathy and central nervous system disorders inboth diabetic and non-diabetic patients. One method of monitoringretinal and neural glucose oxidation is PET (Positron EmissionTomography) scans. Alternatively, one may look forstabilization/reversal of diabetic retinopathy. In terms of neuralfunction, there will be improvement in peripheral neuropathy manifestedas increased perception of sensation, especially in the feet, and a lossof the painful “burning” or “pins and needles” sensation in the feet.There will also be improvement in autonomic neuropathy, especiallygastroparesis and improvement in postural or orthostatic hypotension.

Diabetic heart disease is the one of the more common complications ofdiabetes, experienced by both type I and type II diabetic patients.Experts generally agree that the primary fuel for both the normal anddiabetic heart is free fatty acids, a fuel that requires more oxygen ona per calorie basis than glucose as a fuel. As a consequence, the heartof both diabetic and non-diabetic individuals is particularly vulnerableto ischemia. If the involved tissue had been primarily utilizing freefatty acids for energy generation, even a slight or temporary decreasein blood flow or oxygen supply would be catastrophic. On the other hand,if that tissue had been oxidizing glucose rather than free fatty acids,for the generation of an equivalent amount of energy, a temporarydisruption of blood or oxygen supply would not be as deleterious, sincethat tissue's oxygen requirements would be less. Thus, for the sameamount of oxygen delivered to the myocardium, glucose utilization ratherthan free fatty acid utilization would result in increased energy (ATP)generation. The present invention is capable of improving fuelprocessing capabilities by allowing for more glucose to be burned oroxidized by the heart and correcting over utilization of free fattyacids associated with heart disease and cardiovascular disease in bothdiabetic and non-diabetic patients.

Hepatic processing of glucose includes proper uptake of glucose in theliver cells, oxidation of glucose by the liver cells, storage of glucoseas hepatic glycogen in the liver cells, and conversion of glucose to fator alanine, an amino acid, by the liver cells. Hepatic processing isimpaired when the liver fails to produce hepatic enzymes (such ashepatic glucokinase, phosphofructokinase, and pyruvate kinase) needed inproper glucose processing. Impaired processing of glucose is afundamental condition of type 1 and type 2 diabetic patients, forpatients whose pancreas is not producing sufficient insulin, and forpatients experiencing significant insulin resistance, or a combinationof these factors. After the ingestion of glucose, even with intravenousinsulin administration, decreased glucose oxidation, low alanineproduction, and little glycogen formation and deposition in the liver ina timely manner are all indications that hepatic glucose processing isimpaired. Glucose tolerance tests and measurements of hemoglobin A1c canbe used as indications that hepatic processing of glucose has beenimpaired. The present invention improves the hepatic processing ofglucose.

Further, the present invention is capable of improving the entiremetabolic process, and, through its multiplicity of effects onneurovascular reactivity, intraglomerular pressure and hemodynamics, ofarresting the progression of overt diabetic nephropathy, of improvingintraglomerular hemodynamics, thus arresting the progression of diabeticnephropathy, and reducing the risk of development of ESRD in bothdiabetic and non-diabetic patients.

Still further, the present invention is capable of increasing glucoseoxidation in an affected area and thereby providing more energy with thesame oxygen delivery for treating wounds, promoting healing and avoidingamputations in both diabetic and non-diabetic patients. The rationalefor this improved healing is that the tissue surrounding the affectedarea suffers from inadequate blood supply, leading to insufficientoxygenation. When this tissue is fueled through enhanced glucoseoxidation in lieu of free fatty acid utilization, thereby switching froma predominantly lipid based fuel economy to one based more on glucoseoxidation, more energy is available for wound healing for the sameamount of blood flow and hence, more healing from the amount of oxygendelivered. In addition, the ability to achieve more energy from lessoxygen, thereby addresses a general malaise associated with diabeticindividuals who have energy levels which are less than normal.

On many occasions patients who have been diabetics as well as havingdementia have been treated with the method of the current invention.Dementia appears to be related to poor metabolism of glucose in thebrain, which may well be the result of constricted flow of blood. Thispoor metabolism is at least in part the cause of the dementia. Use ofthe present invention in patients suffering from senile dementia hasclearly shown improvement in confusion, weakness, disorientation,cognitive function and lack of memory associated with dementia as wellas improvement in the blood glucose management. Constricted flow ofblood to the brain is also prevalent in demented patients withoutdiabetes and the method of the current invention provides improvedmetabolism as well to those patients and hence is effective in treatingboth demented patients with and without diabetes.

Glucose oxidation by the brain can be affected in many ways. Forinstance, glucose oxidation by the brain and nerves diminishes as aconsequence of aging or as a result of brain injuries or trauma.Furthermore, jet lag may also lead to a decrease in glucose oxidation bythe brain and nerves. The present invention has clearly shownimprovement in confusion, weakness, disorientation, cognitive functionand lack of memory associated with age, brain injury or trauma and jetlag by improving the glucose oxidation in the brain and nerve tissues.

In the preferred embodiment, with a new patient two successive days ofthree treatments are performed the first week. For continuing patientsthe procedure is performed once a week. For patients who need/require amore intensive approach, the procedure may be repeated 3 or more times,including continuously, each week until the desired clinical outcome isachieved.

The following non-limiting examples are given by way of illustrationonly.

EXAMPLE 1

A study was conducted to assess the effects of Chronic IntermittentIntravenous Insulin Therapy (CIIIT) also known as Metabolic ActivationTherapy (MAT), Hepatic Activation, Pulsatile Intravenous Insulin Therapy(PIVIT), Pulsatile or Pulse Insulin Therapy (PIT) on the progression ofdiabetic nephropathy in patients with type 1 diabetes mellitus (DM).This 18-month multi-center, prospective, controlled study involved 49type 1 DM patients with nephropathy who were following the DiabetesControl and Complications Trial (DCCT) intensive therapy (IT) regimen.Of these, 26 patients formed the control group C, which continued on IT,while 23 patients formed the treatment group (T) and underwent, inaddition to IT, weekly CIIIT. All study patients were seen in clinicweekly for 18 months, had monthly glycohemoglobin HbA1c measurementschecked, and every 3-months, 24 hour urinary protein excretion andcreatinine clearance (CRCl) determinations. CrCl declined significantlyin both groups as expected, but the rate of CrCl decline in the T group(2.21±1.62 ml/min/yr) was significantly less than in the C group(7.69±1.88 ml/min/yr, P=0.0343). The conclusion is that when CIIIT isadded to IT in type 1 DM patients with overt nephropathy, it appears tomarkedly reduce the progression of diabetic nephropathy.

EXAMPLE 2

A middle-aged woman with Type 1 diabetes for more than 22 years sufferedfrom polyneuropathy. She had generalized pain and was unable to walk oreven wear nylon stockings because of the pain. After receiving treatmentwith the subject method, the pain has been reduced to the point wherethe woman enjoys rigorous exercise such as roller blading.

EXAMPLE 3

A middle-aged woman with Type 1 diabetes for more than 30 years hadsevere peripheral neuropathy, was in constant pain below the knees andhad difficulty sleeping at night. After receiving treatment with thesubject method, she no longer takes pain medication and has no twingesof pain in her legs. She has been using the treatment for eight years.

EXAMPLE 4

A middle-aged woman with type 2 diabetes for 17 years was suffering fromsevere dilated cardiomyopathy (ejection fraction 14-19%). She was placedon the list to receive a heart transplant prior to starting treatmentwith the subject method. After receiving treatment, the subject reducedher insulin intake from 150 units a day to 24-26 units/day, and shestabilized to the point where she no longer required a heart transplantand, indeed, was removed from the heart transplant list. The patient hasbeen receiving treatment for 10 years and is still off the hearttransplant list. Her ejection fraction is currently 29-32%.

EXAMPLE 5

A middle-aged male with type 1 diabetes for 38 years suffered frommacular degeneration (retinopathy). He was unable to drive at night.After receiving treatment with the subject method, the man's eyesightimproved to the point where night driving was no longer a concern. Thepatient has been receiving treatment for 4 years.

EXAMPLE 6

A middle-aged type 2 diabetic male patient had severe heart diseaseincluding congestive heart failure and severe artereosclerotic heartdisease. The patient was scheduled for heart surgery but because of hispoor condition, surgeons refused to operate. After using the subjectmethod, the doctors were convinced that he could withstand 4-vesselby-pass surgery. The patient had a normal postoperative recovery, whichis virtually unheard of for diabetic patients with his stage of heartdisease.

EXAMPLE 7

An older type 2 diabetic male patient was exercising and had excellentcirculating glucose control under intense insulin therapy including 3-4injections per day of subcutaneous insulin. Even so, his diabetesrelated kidney disease had progressed to the point where he wasdischarging 1500 milligrams of protein during a 24-hour period and therate of increase was 500 milligrams/24 hours/year. After using thesubject method, the patient's proteinuria was reduced to 600-800milligrams/24 hours. He has been using the method for 5 years.

EXAMPLE 8

An older type 1 diabetic female patient who was diabetic from age 5years old was scheduled for a coronary artery by-pass graft to correcther diabetes related heart disease. The surgeons were reluctant tooperate in the condition she was in because of her advanced diabetesrelated arteriosclerosis. She was scheduled for a single vessel graft.After using the subject method, her condition improved to the pointwhere the doctors performed two instead of one bypass grafts. She had anormal recovery. She continuing using the subject method for severalyears after the surgery with no further deterioration in her diabetesrelated heart disease.

EXAMPLE9

An older type 2 diabetic male suffering with autonomic neuropathy hadvery elevated blood pressure readings of 200/120 despite a rigorousprogram to regulate his circulating glucose using intensive insulintherapy of 3 to 4 subcutaneous insulin injections daily. As a result ofusing the subject method, his blood pressure decreased to 120/80. He hasbeen using the method for 5 years.

EXAMPLE 10

An older type 2 diabetic male patient had one amputated leg as a resultof diabetes related ulcers on that leg. He had developed ulcers on theother leg that would not respond to any available therapy and was indanger of losing the other leg to amputation. As a result of using thesubject method, the ulcers on his second leg healed, and the leg wassaved from amputation. This patient used the subject method for severalmore years, and no additional ulcers formed.

EXAMPLE 11

A middle-aged type 1 female diabetic patient had developed severe ulcerson both legs, which would not heal with any available treatment. As aresult of using the subject method, the ulcers healed and have neverreturned. The patient has been using the subject method now for 13years.

EXAMPLE 12

A middle-aged type 2 male diabetic patient had proliferative diabeticretinopathy with severe bleeding. Multiple photocoagulation scars madeadditional photocoagulation impossible. As a result of using the subjectmethod, the bleeding stopped, and there was no further deterioration ofthe retina, preserving what eyesight he had left. The patient has beenusing the subject method for 5 years, and he has had no further bleedingof the retina and no further photocoagulation.

EXAMPLE 13

An elder type 2 female diabetic patient had severe painful peripheralneuropathy to the point that she was unable to walk and used awheelchair. After six months of using the subject method, the pain hadsubsided to the point where she no longer used a wheelchair. Because offinancial reasons, she stopped the therapy. As a result, the neuropathyreturned, and she returned to using a wheelchair.

EXAMPLE 14

A middle-aged type 1 female diabetic patient had severe neuropathy. Shewas a mother of two children who was bed-ridden with autonomicneuropathy before using the subject method two years ago. Her muscleshad atrophied, she could not digest her food, she had been told that hernerves were dying inside her as a result of her diabetes. She statedthat if she had not had two children, she would have taken her life. Shehad to quit her job, went on disability and was in an out of thehospital very often. She had welts on her head causing hair loss. Shehad no sensation in her feet, she had constant nausea, and she couldn'tsleep at night because of the pain. She had insulin absorption problemsand tried all different ways to improve the absorption of insulin intoher body. For a number of years she injected herself intramuscularlybecause she felt that she obtained the best absorption of insulin thatway. Since using the subject method she has reversed all of the diseasesto the point where she has taken herself off disability and is gainfullyemployed. She has not been in the hospital since. The numbness in herlegs has gone away. If she skips the treatment for a week, she can feelthe numbness return to her legs. Her gastroparesis was reversed, and sheno longer suffers symptoms. Since using the subject method, she has noinpatient medical costs now.

EXAMPLE 15

A 79 year old female diabetic who was suffering from advanced seniledementia was placed in a nursing home because of excessive confusion,weakness, disorientation and lack of memory. Because the nursing homewas not keeping up the strict four shot regimen needed by the patientfor her diabetic blood sugar control, the patient's children removed thepatient from the nursing home. The patient's family doctor recommendedCIIIT. Once the patient was activated, she returned to a totallyindependent living style. She had significant improvement in her motorskills, memory, and cognitive function. CIIIT clearly had a positiveeffect on her senile dementia.

EXAMPLE 16

A non-diabetic older physician had noted a progressive decline in hisability to promptly recall diagnoses/medical facts relating to hispatients' illness. In addition, he reported that he suffered from “jetlag” and when traveling, required 5-7 days at his destination before hefelt “normal”. He underwent CIIIT (3 treatments for only 1 day permonth), and reported a prompt restoration of his ability to recallappropriate diagnoses and medical facts relating to the patients' thathe was seeing. In addition, he reported the immediate reversal of his“jet lag”.

For all of the above listed examples, after the initial few days oftreatment, the patients underwent treatment once a week, each treatmentday consisting of three infusions of insulin accompanied by ingestion ofcarbohydrates. The infusion device used to infuse the insulin was theBIONICA MD110 pump. Typically there were ten pulses given over a periodof one hour, and a rest period of one hour was taken between infusionsof insulin. The form in which the carbohydrates were ingested changedfrom time to time and included eating foods of high glycemic indexincluding but not limited to bread, rice, potato, pasta, and cake. Thepatients' circulating glucose were measured once every thirty minutes bythe finger stick method currently used by most diabetic patients.Circulating glucose levels initially rose by 100-150 mg/dl during thefirst treatment and then fell between 50 and 100 mg/dl second and thirdtreatments indicating that total body tissue glucose processing had beenactivated. Table 1 below summarizes by the above examples the number ofunits of insulin per pulse administered and the amount of glucoseingested for each series of pulses.

The preferred embodiments described herein are illustrative only, andalthough the examples given include many specificity's, they areintended as illustrative of only a few possible embodiments of theinvention. Other embodiments and modifications will, no doubt, occur tothose skilled in the art. The examples given should only be interpretedas illustrations of some of the preferred embodiments of the invention,and the full scope of the invention should be determined by the appendedclaims and their legal equivalents.

TABLE 1 TABLE 1 Summary of the above examples: The number of units ofinsulin per pulse administered and the amount of glucose ingested foreach series of pulses Number of milliunits of Example insulin/Kg of bodyweight Grams of Glucose per Series Number per Pulse of Insulin Pulses. 1*  15-195 40-100 grams 2 30-45 50-60 grams 3 35-50 40-60 grams 4 45-6040-60 grams 5 30-45 50-60 grams 6  70-100 50-70 grams 7 40-60 50-70grams 8 15-45 50-70 grams 9 40-55 50-70 grams 10  45-60 40-60 grams 11 15-45 50-70 grams 12  130-170 50-70 grams 13  30-60 50-70 grams 14 30-60 50-70 grams 15  30-60 50-70 grams 16  10-30 70-100 grams*This study included 23 patients in the treatment group with varyingamounts of insulin per pulse and varying ingestion of glucose. Hencegeneral limits of what they used are included.

1. A system for infusing insulin to a subject to improve impaired totalbody tissue glucose processing comprising: a. a blood glucose monitorfor determining a steady baseline circulating glucose level of thesubject and obtaining a subsequent circulating glucose level at leastevery 30 minutes, the steady baseline circulating glucose level beingtwo consecutive circulating glucose levels about 200 milligrams perdeciliter measured five minutes apart, b. a carbohydrate containingmeal, the carbohydrate containing meal containing 40 to 100 grams ofglucose being consumed by the subject and, c. a means for administeringa quantity of insulin through an intravenous site until the subsequentcirculating glucose level shows an improvement over the steady baselinecirculating glucose level, the improvement over the steady baselinecirculating glucose level being a 50 milligram per deciliter or morefall from the steady baseline circulating glucose level withinapproximately two hours of administering the quantity of insulin, thesubsequent circulating glucose level improvement over the steadybaseline circulating glucose level being a measurement of sufficientquantity of insulin to achieve an improvement in total body tissueglucose processing, wherein the improvement in total body tissue glucoseprocessing occurs as a result of total body tissue response to a rate ofchange in insulin level and an absolute increase in peak and interpeakfree insulin levels.
 2. The system of claim 1 wherein the intravenoussite further comprises a needle or catheter located in the subject'sbody, hand or forearm.
 3. The system of claim 1, wherein the means foradministering a quantity of insulin delivers 10 to 200 milliunits ofinsulin per kilogram of body weight.
 4. The system of claim 1, whereinthe means for administering a quantity of insulin delivers insulin every3 to 30 minutes.
 5. The system of claim 1, wherein the means foradministering a quantity of insulin delivers insulin as a series ofpulses.
 6. The system of claim 5, wherein the series of pulses isperformed 2 to 8 times a day.
 7. The system of claim 1, wherein themeans for administering a quantity of insulin is an intravenous infusiondevice.
 8. The system of claim 1, wherein the means for administering aquantity of insulin is a syringe.
 9. The system of claim 1, wherein themeans for administering a quantity of insulin is a programmableprocessing unit, the programmable processing unit capable of controllingthe quantity of insulin at a specified rate of delivery.
 10. The systemof claim 1, wherein the intravenous site is converted to a heparin orsaline lock when the administration of insulin pulses has temporarilyceased between treatments.
 11. The system of claim 1, wherein the bloodglucose monitor and the means for administering a quantity of insulinare connected by a communication link.
 12. The system of claim 1,wherein the improvement in total body tissue glucose processing is usedto lower levels of hemoglobin A1c.
 13. The system of claim 1, whereinthe improvement in total body tissue glucose processing is used to delaythe onset or slow the progression of diabetes related nephropathy. 14.The system of claim 1, wherein the improvement in total body tissueglucose processing is used to delay the onset or slow the progression ofdiabetes related retinopathy.
 15. The system of claim 1, wherein theimprovement in total body tissue glucose processing is used to delay theonset or slow the progression of diabetes related neuropathy.
 16. Thesystem of claim 1, wherein the improvement in total body tissue glucoseprocessing is used to delay the onset or slow the progression ofcardiovascular disease.
 17. The system of claim 1, wherein theimprovement in total body tissue glucose processing is used to delay theonset or slow the progression of heart disease.
 18. The system of claim1, wherein the improvement in total body tissue glucose processing isused for treating wounds, promoting healing and avoiding amputations indiabetic subjects.
 19. The system of claim 1, wherein the improvement intotal body tissue glucose processing is used to improve mental functionin subjects with senile dementia.
 20. The system of claim 1, wherein theimprovement in total body tissue glucose processing is used to improvemental function in subjects having a decreased glucose oxidation ratedue to aging, brain injury, brain trauma or jet lag.